Targeting long-term depression of excitatory synaptic transmission for the treatment of neuropathic pain

Injury or disease in the somatosensory nervous system may cause broad molecular changes and lead to neuropathic pain. Excitatory synaptic transmission in somatosensory pathways conveys the somatosensory information from the peripheral to the central nervous system. Long-term effects of excitatory synaptic transmission on the pain pathway contribute to neuropathic pain hypersensitivity. Synaptic strength is dynamically regulated and undergoes bidirectional changes, manifested by two primary forms of synaptic plasticity, long-term potentiation and long-term depression (LTD), which are mediated by insertion and endocytosis of amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs), respectively. Molecular mechanisms of LTP have been extensively studied; on the other hand, the role of AMPAR endocytosis in the pain-related synaptic enhancement is less well known. Recent research in the anterior cingulate cortex reveals that loss of LTD contributes to the maintenance of neuropathic pain, which provides the novel perspective of the mechanism of LTD also being critical for maintaining neuropathic pain. More importantly, exploring the molecular mechanism of LTD may help with the development of novel analgesic strategies to manage neuropathic pain.

Automated summary

Injury or disease in the somatosensory nervous system can lead to neuropathic pain through changes in excitatory synaptic transmission. The regulation of synaptic strength and bidirectional changes play a role in neuropathic pain hypersensitivity, with long-term potentiation and long-term depression being key forms of synaptic plasticity. Understanding the molecular mechanisms of LTD may offer insights into the development of novel analgesic strategies for managing neuropathic pain.